Arrangement for removing substances from liquids, in particular blood

ABSTRACT

The present invention is directed to an arrangement for the elimination of substances by means of a membrane filter wherein the use is foreseen both in the blood cleaning procedures as well as in chemical and biotechnological separation techniques. The fluid containing the substances is run through the primary side of the membrane filter and the secondary side is flowed through by a adsorptive suspension which contains the substance binding particles. A pump drives the adsorptive suspension through the secondary side of membrane filter and causes in this way locally differentiable positive and negative transmembrane pressure differences whereby a local fluid exchange occurs and by means of which the active substances come into contact with the particles. Since the volume of the adsorptive suspension in the secondary circuit is held constant, the mean transmembrane pressure does not alter.

This application is a 371 of PCT/EP94/02644 filed 8/10/94.

FIELD OF THE INVENTION

Arrangement for the elimination of substances from fluids

BACKGROUND OF THE INVENTION

The invention is directed to an arrangement for the elimination ofsubstances from fluids in particular blood which comprises in the firstcircuit wherein the fluid to be treated flows, an attachable membranefilter and in whose secondary, for example, filtrate side there is asuspension containing an adsorbent for binding those substances passingthrough the membrane.

The elimination of patho-physiologically relevant substances can becarried out with extra corporeal systems, wherein membrane filters andadsorption procedures may be utilized. Included in such processes theremay particularly be mentioned hemodialysis, high-flux hemodialysis,hemofiltration, membrane plasma separation, hemoperfusion and plasmaperfusion. For special purposes, for example, the therapy of liverfailure, hybrid systems which comprise the provision of special celltypes such as hepatocytes, are in clinical trial. For example, suchtherapeutic procedures are utilized for chronic kidney insufficiency,acute exogenic intoxication, acute and chronic liver insufficiency,endotoxin shock, metabolic disturbances, hyperlipidemia, and auto immunediseases. With respect to the presently known pathophysiologicallyrelevant substances, one is concerned with a substantial spectrum ofdifferent substances having different chemical(protein-lipid-waterbound, hydrophilic, hydrophobic) and differentphysical properties (molecular size, molecular weight) for which reasondifferent procedures must be utilized.

DISCUSSION OF THE PRIOR ART

In order to eliminate substances such as LDL-cholesterol, endotoxins,antibodies, antigens, and protein/lipid bound materials in a selectivemanner, it is preferred to utilize adsorption protected procedures. Thedisadvantages of such systems is as follows:

The difficulty of applying a system which guaranties blood contactbecause of the problem of blood compatibility, in particular wherefinely divided adsorbents are concerned.

With plasma perfusion as is illustrated in FIG. 1, a filtrate is pumpedout from filter (1) through exit (6) into the secondary circuit (12) bypump (13). The filtered plasma then flows through a capsule (41) whichcontains particles binding the effective material. Then the cleanedplasma flows back to the patient 31 through primary circuit (11). Thisprocedure is very costly economically and technologically. Because ofthe limited binding capacity of particles in capsule (41), it isnecessary to regenerate or flop them out during the use under clinicalconditions.

While it is desirable to utilize the smallest possible particles sincethese give rise to the largest surface area, however, the use of suchsmaller particles in capsule (41) leads to higher packing densities andthus to higher flow resistance which give rise to a very substantialpressure drop between input (42) and output (43).

Furthermore, because of the plasma removal in filter (1), there is athickening of the blood in vicinity of the exit of the membrane filterwhich gives rise to risks of blood clot formation.

Because a mechanically reliable binding of the particles in capsule (41)cannot be absolutely guarantied, for safety reasons a further filter isprovided before input into the patient through input (9).

Where there are utilized suspensions containing adsorptive material inthe known procedures (for example, biologic DT, PCT WO93/15825 Ash andU.S. Pat. No. 5,078,885, Matsomura) reliance is principally made on theknown principles of diffusion. Therein there are either utilizedselective procedures such as the use of asymmetrically constructedmembranes in combination with the correspondingly formed and thereforevery expensive adsorbent particles or the use of expensive pumpingsystems to obtain the pulsing forwarding and turn over of thesuspension. Thus, both procedures are associated with high costs.

An arrangement for the elimination of substances set comprising a firstand a second fluid circuit having at least one membrane filtertherebetween capable of allowing passage therethrough of the substancesto be eliminated, said membrane having a primary side in said firstcircuit and a secondary side in said second circuit, said fluid to bepurified being located in said first circuit and said second circuitcomprising an adsorbent containing suspension of particles for bindingsaid substances to be eliminated, a first pump located in said firstcircuit for circulation of the fluid to be purified, and a second pumplocated in said second circuit for circulation of the adsorbentcontaining suspension, is known from U.S. Pat. No. 3,963,613. The knownarrangement permits the removal of selective substances by the use ofdialysate by means of different enzymes, which are present in thesuspension or may be encapsulated. In a preferred embodiment, the knownarrangement utilizes two dialysers switched in parallel, wherein onechamber of the second dialyzer is not connected in a fluid circuit.

The known arrangement is directed solely to the diffusive elimination ofa low molecular substances.

EPAO 143178 describes an arrangement for blood purification with afilter whose primary compartment is switched into the blood circuit andwhose secondary compartment is switched into a secondary circuit intowhich an adsorption capsule is connected. An adsorbent containingsuspension is not present in the second circuit. The achievement oflocally differing positive and negative transmembrane pressure resultssolely from raising of the flow rate of blood in the primary circuit.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide an arrangement of thetype mentioned in the prior art, wherein substances may be removed fromthe fluid in particular from blood with a higher sale activity andhigher adsorptive efficiency, this particular problem is solved byproviding that the second pump is drivable at a forwarding speed so thatthere is a passage of the substance containing fluid across the membranefilter between said first and second circuits, said pump in said secondcircuit being a means for achieving regionally occurring differentiablepositive and negative transmembrane pressure on said membrane.

In the arrangement in accordance with the present invention the medium,in particular blood, containing the substance to be eliminated is ledthrough a membrane filter in particular a plasma filter or a hemofilterwhich is divided on the one side into a blood chamber and on the otherside into a filtrate chamber. Herein the blood chamber is the primaryside to which, in the conventional manner, blood is led via a firstpump, suitably a peristaltic pump.

The filtrate chamber which comprises the secondary side, that is to saythe filtrate side, is loaded with a cleaning suspension which containsparticles which are enabled to bind the substance to be removed. Thisfluid as is conventional further comprises an electrolyte havingisotonic composition.

Thus, the cleaning suspension is run through the filtrate chamber of themembrane filter at forwarding speed by means of a second pump which isprovided in the secondary circuit.

Furthermore, it is important with respect to the present invention thatthere is a means for obtaining different positive and negativetransmembrane pressures at different areas of the membrane. This is mostreadily carried out with the so-called high-flux membranes which arecommercially available in many different forms. These characterizethemselves by a high water permeability in dependence on the surfacearea of the membrane, the pressure, and the treatment time. Suchhigh-flux membrane filters, at room temperature, have a permeability forwater of the order of 15 to 20 mm per hour X m² ×mm and more.

By reason of the flow conditions of the cleaning suspension on the outerside of the filter membrane, conventionally constructed from hollowfibers, there occurs a pressure drop between the inflow side and theoutflow side of the filtrate chamber which has the consequence that at asufficiently high input pressure which is substantially determined bythe flow speed and the flow resistance of a medium in the filtratechamber, fluid may be forced through the pores of the membrane into theblood path.

Generally speaking, the secondary volume is constant which has theconsequence that on the opposite side the same conditions occur inreverse sequence, that is to say, that a back filtration occurs of thefluid volume previously passed through the membrane. It is advantageousif the membrane filter is run in a counter-current fashion, that is tosay, the two fluids flow through each chamber in opposite directions.Thus, at the input of the chamber, there is a positive pressure, whichis correlated at the output of the chamber with a negative pressure.During the cleaning of blood, this has the consequence that blood plasmatogether with the substances to be eliminated on the blood input side,move through the membrane to the filtrate side where they are freed fromthe substance to be removed and again returned to the opposite sidebecause of the balancing of the blood circuit.

It is furthermore important to the present invention that the volume ofthe secondary circuit is held in balance which conventionally occurs byholding the volume of the secondary circuit constant.

It is advantageous that the pump in the secondary circuit is combinedwith a means for obtaining a different transmembrane pressure whichoccurs because the pump is driven with the appropriate input pressure torelatively high through-put rates of 0.5 to 6, suitably 1-3 liters/min.

It is further advantageous to provide that the pump utilized forforwarding the suspension in the secondary circuit is a centrifugal pumpwhich is characterized by a low mechanical shear loading with respect tothe suspended adsorption particles. Thus, there occurs a very minimalmechanical damage of these particles during the pumping process.

In a further advantageous embodiment, there is provided, in addition tothe first membrane filter, a second membrane filter in series with thefirst membrane filter so that both blood chambers and filtrate chambersare sequentially flowed through by blood and cleaning suspension. Thisarrangement leads to an increase in elimination efficiency since anadjustable clamp is provided in the connection line between the filterson the filtrate side, as a further means for achieving differenttransmembrane pressures.

As previously mentioned, the secondary circuit is provided with abalancing arrangement wherein the amounts of fluid lead in and lead outmay be balanced. Such a balancing arrangement can be provided by twosimilarly driven forwarding arrangements (pumps), wherein one isprovided to the input branch and the other to the output branch of thecircuit. This pumping arrangement (for example a double hose pump) caninput and output identical amounts of cleaning suspension. On the otherhand, a balancing chamber system may also be utilized as it isdescribed, for example, in German patent DE 28 38 414 and is utilized inmany balanced hemodialysis arrangements.

It is preferred that the cleaning suspension is only run through thesecondary circuit until its elimination capacity is almost exhausted.Furthermore, it is desirable that the exhausted cleaning suspension is,if possible, not mixed with fresh cleaning suspension, which may beadvantageously achieved by means of a blocking valve which prevents suchmixing. Furthermore, a pump may be provided to accelerate this exchange.

A plurality of components coming into contact with biological fluids inparticular blood, are formed for but a single utilization (so-calleddisposables) wherein, for example, the pump utilized in the secondarycircuit is comprised of a replaceable drive portion and a single usepump head.

Furthermore, the arrangement of the present invention advantageouslycomprises detectors for recognition of defects in the filters which aremanifested in the fluid of the primary circuit. Included in suchdetectors are ultrasound detectors, photo-optical sensors which canreport photo-optically detectable substances, magnetic sensors which canreport magnetically active materials and the like.

In accordance with another embodiment a fabric filter is provided afterthe output of the membrane filters so that in the event of a defectpermitting the passage of adsorption particles, these are detected andheld back before their entry into the blood path of a patient.

Furthermore, after the output of the primary side of the membranefilter, there may be provided a magnetic field which can deflectmagnetically active materials which present as particles in the cleaningsuspension, whereas these particles arrive in the primary side due to adefect in the membrane filter.

It is furthermore advantageous if pressure sensors are provided to theinput and output sides of the chambers of the membrane filters so thatthe transmembrane pressure may be reported over the entire membrane andthus the two pump levels which are the means for achieving differentmembrane pressures can also be controlled in a predetermined manner.

The particles provided in the cleaning suspension are selected withreference to the substance to be eliminated. Thus, for example thearrangement of the present invention is particularly suitable for theremoval of endotoxins or other mediators including cytokines such as theTumor-Necrose factor or Interleukin 1. The particles thus have a veryhigh adsorption capacity which is characterized by a surface coveredwith large amounts of the substances. It is particularly advantageous touse the so-called microspheres which generally have a diameter ofbetween 5 and 50 μm.

If it is desired to remove endotoxins from plasma, one has to ensurethat these, by virtue of their phosphate groups are loaded inphysiological media (blood pH 7.36-7.44). Therefore, adsorber matricescontaining cationic substances should be used. Cellulose beads areparticularly advantageous when they are modified with cationicsubstances, for example with diethylaminoethyl groups or withpolyethylene imine groups.

In a totally different clinical area, for example, the therapy ofhyperlipid-demia, the technology of the present invention may beutilized for LDL adsorption. Also here, cellulose beads, suitably with adiameter of 5 μm may be utilized.

There may also be used natural cells such as fibroblasts or the likewhich show no metabolic or morphological damage after 5 hours of runningthrough secondary circuit.

It has been determined that for the success of the arrangement of thepresent invention, it is only necessary that the cleaning suspension ispumped through the secondary chamber of the membrane filter in abalanced manner, that is to say, with such an input pressure that on oneside of the filter, filtered cleaning suspension is lead over into theblood chamber and on the other side, the same volume of plasma istransported onto the filter side.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing illustrates the invention in connection with the followingworking examples.

They show:

FIG. 1--A plasma perfusion arrangement;

FIG. 2--A first embodiment of an arrangement in accordance with thepresent invention for the elimination of substances from blood;

FIG. 3--A second embodiment of an arrangement in accordance with thepresent invention set forth in schematic format;

FIG. 4--The principle arrangement of a detector for the reporting ofmagnetically active particles;

FIGS. 5 and 6--are cross sectional views of a hollow fiber membranefilter with the same distribution of hollow fibers inside the housing;

FIG. 7--A further embodiment of an arrangement of the present inventionin schematic format showing two membrane filters;

FIGS. 8 through 10--are curves of experiments utilizing the arrangementof the present invention wherein the ordinates show the amounts ofsubstance to be removed and the abscissae show the time taken.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 2 shows the principle elements of the invention; the primarycircuit (11) of the arrangement guides venous or arterially sourcedblood of patient 31, that is to say, the fluid to be cleaned, via a hose(8) to the input (3) of the primary side (2) of the membrane filter (1)and further from output (4) of the membrane filter (1) over the hose (9)back to the patient or recipient. In order to maintain or increase theflow in the primary circuit, there may be provided a pump (10). Thesecondary circuit (12) of the arrangement is filled with a cleaningsuspension which comprises the particles binding the active substancewherein the carrier fluid in the suspension can have active effects andcan further comprise active substances in the known manner such as, forexample, albumin. The cleaning suspension is driven by a pump (13)through the secondary circuit (12) wherein this pump may not damage theparticles (14) mechanically, thermically or chemically. A pump should beutilized which has minimal shearing effect. This may be particularlyobtained with a centrifugal pump. The pump moves the cleaning suspensionthrough input (5) of the secondary side (7) of membrane filter (1),whereby the cleaning suspension exits through exit (6). Because of theflow and current resistance of the membrane filter, pressure differencesarise between input (3) and output (4) on the primary side (2) as wellas between input (5) and output (6) on the secondary side. There thusarises locally differentiable transmembrane pressure differences betweenthe primary and secondary side in the vicinity of the primary input (3)and the secondary output (6) between the primary side and secondary side(designated as positive) and in the vicinity of the secondary input (5)and the primary input (4) between the secondary side and the primaryside (designated as negative). This leads to an exchange of fluidcontaining active substances moving through the filter membrane (33)between the primary and secondary side. Where the circulating volume ofthe cleaning suspension of the secondary circuit (11) is held constant,in the stationary condition there can be no permanent volume shiftsince, for example, an excessive transfer of fluid onto the primary side(2) would lead to an under pressure on the secondary side (7) and thusagain to an overflow of fluid onto the secondary side (7). This has theconsequence that in maintaining the volume of the secondary circuit (12)constant, the mean transmembrane pressure must be zero.

At the same time, the local transmembrane pressure differences willrise, both through a rise in the flow of the primary circuit (11), aswell as through the rise of the flow in the secondary circuit (12),which increases the flow exchange and thus the elimination rate. Thedesired local pressure gradients to an effective filtration for medicalpurposes lie 1 and 20 kPa. In utilization in chemical and biotechnicalseparation techniques, even higher local pressure gradients may beprovided. Instead of the countercurrent principle illustrated in FIG. 2,in which the flows on the primary and secondary side are opposed to eachother, one may also utilize the costreaming principle with flows runningin the same direction.

By achievement of these local different pressures gradients, the presentinvention is basically distinguishable from the known devices (forexample Biologic DT) in which a suspension is circulated at a rateinsufficient to achieve such gradients.

FIG. 3 illustrates an arrangement with possible expansions for theimprovement of efficiency and security.

For replacing the cleaning suspension saturated with the activesubstance there may be provided an arrangement wherein the cleaningsuspension is either renewed continuously with a evenly running pumpingsystems or discontinuously. In order to maintain the volume of thesecondary circuit (12) as constant, there may be provided a double-hosepump (20) or another pump system with two similar forwardingarrangements, which pump the new cleaning suspension from reservoir (16)and a conduit (17) into the secondary circuit (12) and from these, thepreviously utilized cleaning suspension through exit (18) leads theused-up cleaning suspension into reservoir (29). In place of thedouble-hose pump, there may be utilized an arrangement of valves ininput (17) and exit (18) wherein additionally there may be provided asingle pump for accelerating the exchange. In order to reduce the mixingof old and new cleaning suspensions, there may additionally be provideda blocking valve (19) which prevents the recirculation in secondarycircuit (12) during the discontinuously effected exchange. Furthermore,for the improvement of the exactness of the balancing, there may beprovided conventionally known arrangements such as weight and volumemeasuring devices or balancing chambers for the input and output pumpingwith the same forwarding volume.

In order to avoid contamination of the arrangement during clinical useby re-use and to avoid subsequent damage to patient 31 all parts incontact with the blood or in contact with the cleaning solution aregenerally speaking single use articles, which are only used once. Thisis achieved in the pump by division into a single use pump head (25) anda reusable drive (26) which are magnetically coupled in a conventionalmanner or which are connected to each other by an insulated shaft.

In order to ensure the security of the patient in the event of failureof membrane filter (1) for example by a rupture of the membrane, it isat a minimum necessary to avoid the entry of particles (14) into theblood circuit and thus into the primary circuit (11) or at least detectthem. Where the particles (14) are substantially bigger than the bloodcomponents, this can be achieved in a conventional manner by a fabricfilter (24) which prevent the entry of particles (14) into patient 31.Where the particles (14) are of a similar size or order of magnitude asthe blood components, a detector (23) should be provided into theprimary circuit in order to close down the arrangement. This detectorcan be provided for the recognition of inhomogeneities in the blood byultrasound or may be photo-optically sensitive wherein the cleaningsuspension is colored with a material recognizable by the detector(coloring materials which absorb in the visible or not visible spectrum,luminescent, fluorescent or phosphorescent materials). A furtherpossibility for the filtration removal of particles (14) exists in theprovision of a magnetic field in utilization of magnet activatable partsof particles (14). The magnetic field drives the particles (14) whichintrude into primary circuit (11) into a trapping arrangement (30) wherethey are held. Such a trapping arrangement may also be provided in thesecondary circuit.

Furthermore, a conventional detector (22) may be provided in thesecondary circuit (12) for the recognition of erythrocytes and/or freehemoglobin. The presence of erythrocytes in the secondary circuit wouldsignal a membrane rupture while free hemoglobin signals the destructionof erythrocytes, for example because of excessively high pressuredifferences. In order to avoid high pressure differences, pressuresensors (27) may be provided in the entry and/or exit lines (3,4,5,6) ofmembrane filter (1). These can be coupled to signal devices which wouldadvise the user with respect to setting the pumping speeds and withrespect to the condition of the membrane filter (for example, thefiltration arrangement) and other parts of the arrangement. This settingof the pumping speed can also be provided with an automatic controlarrangement (28) for the assistance of the user.

In order to avoid an uneven distribution of particles in the cleaningsuspension and in particular in reservoir (16), there may be provided avibration or rocking arrangement.

For particular purposes, for example the replacement of eliminatedsubstances by therapeutically indicated substances such as albumin, thecleaning suspension may be loaded with such therapeutical substances.Furthermore, by a deliberately arranged imbalance between the input andoutput of the cleaning suspension in and from the secondary circuit(12), a fluid transfer into or out of patient 31 may be arranged whenthis appears necessary for volume substitution during blood loss or thereduction of edema.

In FIG. 4 an embodiment of detector (32) is illustrated in the form of awinding (36) around hose (9) in order to hold magnetically activeparticles. These particles induce a potential in winding (36) when theypass this.

In order to increase sensitivity the hose or the conduit may be leadthrough the detector (23) at a smaller diameter than the rest of theconduits of the primary side (11), whereby an improvement in thesensitivity is achieved by the higher flow rate.

Furthermore, the sensitivity may be improved and the security increasedwhere a plurality of such windings (36) are sequentially placed aroundthe hose, or next to hose (9) for the detection of perturbation fields.

In FIGS. 5 and 6 embodiments of membrane filter (1) are shown incross-section in which the membranes in the form of hollow fibers aredistributed in an uneven manner over the inner surface of housing (34).

In accordance with FIG. 5, a channel (35) is provided which runs openlyalong the entire length of membrane filter (1) which allows for freepassage of the cleaning suspension. Alternatively, in accordance withthe illustration of FIG. 6, there is an embodiment showing a pluralityof free channels (37) provided between the hollow fiber membranes (33).

A particularly preferred embodiment of the arrangement of the presentinvention is illustrated in FIG. 7 which may be differentiated from theembodiment of FIG. 1 only therein that instead of a single membranefilter (1) there are provided two membrane filters (1 and 1a) which areconnected with each other by connection conduit (44) for the primarycircuit and by connection conduit (45) for the secondary circuit. It isparticularly advantageous to provide an adjustable clamp (46) in thelatter combining circuit (45) as indicated by the arrow so that upstreamof the clamp, a predetermined over-pressure may be provided which iscorrelated with corresponding under-pressure in the plasma filter (1)because of the balancing of the secondary circuit. This leads inmembrane filter (1) in a predetermined manner to a transfer of aparticular plasma volume into the secondary chamber where theelimination of the substance to be eliminated will occur. In the secondmembrane filter the same volume is lead back into the blood circuit (4).Because of the controllability of the clamp (46) therefore, one maypreset the exact volumes to be handled.

One may further improve the system vis a vis the elimination efficiencyof the single filter arrangement of FIG. 2 by the provision of twoseries provided filters (1 and 1a and 1b) in accordance with FIG. 7.

EXAMPLES 1 THROUGH 3 Example 1

In a batch experiment 18 ml of porcine plasma containing 2 ml ofadsorbent are provided in a capillary plasma filter based onpolypropylene (type P2 or P2S of the company Fresenius) with a membranesurface of 0.5 m². The secondary circuit comprises an endotoxin in theform of a lipopolysaccharide of Pseudomonas aeruginosa serotype 10 Habsin am amount of 20 mg/ml plasma. The total protein content is 4.3 g/dlplasma. It is incubated at 37° C.

FIG. 8 illustrates the relative endotoxin activity and percent againsttime wherein the upper line serves as control, that is to say, thesecondary circuit contains no adsorption particles. The curves lyingthereunder are directed to adsorption particles PEI (polyethyleneimine)as well as PEI cellulose (polyethyleneimine derivatized cellulose beads)and DEAE cellulose beads (diethylaminoethyl derivatized cellulosebeads). The beads themselves (ca 10-20 μm) have a high adsorptioncapacity is due to the high level of coating on the surface of theparticles.

From FIG. 8, it may be noted that the beads can eliminate at least halfof the endotoxin amounts while DEAE cellulose removes more than 90% ofthe endotoxin within 10 minutes.

Example 2

In FIG. 9 there is illustrated a similar endotoxin elimination whereintwo filters corresponding to the embodiment of FIG. 7 are utilized. Thetotal filter surface is 0.3 m² wherein hollow fiber membranes ofpolypropylene are utilized. 1.7 l of human plasma are provided to theprimary side to which 40 mg/ml of endotoxin of Pseudomonas aeruginosaare added and incubated at 37° C. The full speed of the primary sideruns at 0.2 l/min. and on the secondary side at 14 liters/min. To thesecondary circuit, there are provided 90 ml. of modified PEI cellulosein 120 ml. of isotonic electrolyte solution.

The diagram illustrates that upon the addition of the micro beads (ca5-10 mm diameter) the endotoxin concentration falls rapidly wherein thisfall is illustrated in two tests. From this it may be seen thatvirtually all of the endotoxin is eliminated within half an hour.

Example 3

Example 3 shows another treatment process in accordance with the presentinvention wherein not only endotoxin but a plurality of other particlesare removed by the choice of suitable adsorbents. In FIG. 10 there isillustrated the removal of triglycerides (LDL) in a two-filter versionof FIG. 7. Again there are utilized polypropylene hollow fiber membraneswith a total surface of 0.3 m². Into primary circuit there is pumped 1.7liters of human plasma with a total protein content of 5 g/DL at 37° C.with a flow rate of 200 ml/min. The secondary side comprises anadsorbent for unmodified cellulose beads (R94/29) in isotonicelectrolyte solution wherein the adsorbent is added in 140 ml portionsat 120, 160 and 210 minutes (see the arrows in the Figure). The flowrate on the secondary side is 14 l/min. The secondary circuit contains300 ml. of fluid. The LDL is determined by conventional methods.

From FIG. 10 it may be seen that the amount of triglycerides in theprimary circuit is reduced in dependence upon the addition of adsorberbeads.

We claim:
 1. An arrangement for the elimination of substances from afluid to be purified, comprisinga first and a second fluid circuithaving at least one membrane filter therebetween capable of allowingpassage therethrough of the substances to be eliminated, said membranefilter having a primary side in said first circuit and a secondary sidein said second circuit, said fluid to be purified being located in saidfirst circuit and said second circuit comprising an adsorbent containingsuspension of particles for binding said substances to be eliminated, afirst pump located in said first circuit for circulation of the fluid tobe purified, and a second pump located in said second circuit forcirculation of the adsorbent containing suspension, wherein said secondpump is drivable at a forwarding speed so that there is a passage of thesubstance containing fluid across said at least one membrane filterbetween said first and second circuits, said pump in said second circuitbeing a means for achieving regionally occurring differentiable positiveand negative transmembrane pressure on said membrane filter of 1-20 kPawherein two membrane filters are provided, the membrane of each filterhaving a primary side and a secondary side, the primary side of thefirst membrane filter and the primary side of the secondary membranefilter are connected in series by as first connection conduit and thesecondary side of the first membrane filter and the secondary side ofthe second membrane filter are connected in series by a secondconnection conduit.
 2. The arrangement according to claim 1 wherein thesecond pump directs the flow in countercurrent fashion relative to saidfirst pump.
 3. The arrangement according to claim 1 wherein the secondpump has a forwarding capacity of between 0.5 to 6 l/min.
 4. Thearrangement according to claim 3 wherein the second pump has aforwarding capacity of between 1-3 l/min.
 5. The arrangement accordingto claim 1 wherein said second pump is a centrifugal pump.
 6. Thearrangement according to claim 1 wherein all of the parts coming incontact with the adsorbent suspension are provided to be single usecomponents.
 7. The arrangement according to claim 6 wherein the pumpscomprise a reusable drive and a single use pump head.
 8. The arrangementin accordance with claim 1 wherein pressure sensors are provided at atleast one of the inputs and outputs of the membrane filter.
 9. Thearrangement in accordance with claim 1 wherein the adsorbent suspensioncomprises active substances which are introducible into the secondcircuit by an exchange process, in addition to the particles for bindingthe relevant pathophysiological substances.
 10. The arrangementaccordance to claim 1 wherein there is provided a controllable clamp insaid connection conduits.
 11. The arrangement according to claim 1wherein there is provided an inlet and outlet in said second fluidcircuit, the inlet being in fluid communication with means forintroducing fresh adsorbent suspension into said second fluid circuitand the outlet being in fluid communication with means for talking outtherefrom an equal amount of used suspension for the exchange of usedsuspension with fresh suspension.
 12. The arrangement according to claim11 wherein the means for introducing fresh adsorbent suspension andtaking out used suspension having pump means.
 13. The arrangementaccording to claim 11 wherein the means for introducing fresh adsorbentsuspension and taking out used suspension having valve means.
 14. Thearrangement according to claim 11 wherein there is provided a lockingvalve in said second fluid circuit between the inlet and outlet of saidsecond circuit to prevent the mixing of the fresh and the used adsorbentsuspension.
 15. The arrangement according to claim 11 wherein there isprovided a pump means in said second fluid circuit between the inlet andoutlet of said second circuit for the acceleration of passage of fluidacross the membrane.
 16. The arrangement according to claim 11 whereinsaid means for introducing fresh adsorbent suspension into said secondfluid circuit and said means for taking out therefrom an equal amount ofused suspension comprises a control arrangement which enables differentvolumes of input and output of the adsorbent suspension into and fromthe second fluid circuit respectively.
 17. The arrangement in accordancewith claim 11 having a control arrangement which enables differentvolumes of input and output of the adsorbent suspension into and fromthe second fluid circuit.
 18. An arrangement for the elimination ofsubstances from a fluid to be purified, comprisinga first and a secondfluid circuit having at least one membrane filter therebetween capableof allowing passage therethrough of the substances to be eliminated,said membrane filter having a primary side in said first circuit and asecondary side in said second circuit, said fluid to be purified beinglocated in said first circuit and said second circuit comprising anadsorbent containing suspension of particles for binding said substancesto be eliminated, a first pump located in said first circuit forcirculation of the fluid to be purified, and a second pump located insaid second circuit for circulation of the adsorbent containingsuspension, wherein said second pump is drivable at a forwarding speedso that there is a passage of the substance containing fluid across saidat least one membrane filter between said first and second circuits,said pump in said second circuit being a means for achieving regionallyoccurring differentiable positive and negative transmembrane pressure onsaid membrane filter, wherein there is provided a detector located insaid first circuit after the output of the primary side of the membranefilter, for noting defects in said filter, wherein the detector is anultrasound filter which recognizes the presence of particles in thefluid of the first circuit.
 19. An arrangement for the elimination ofsubstances from a fluid to be purified, comprisinga first and a secondfluid circuit having at least one membrane filter therebetween capableof allowing passage therethrough of the substances to be eliminated,said membrane filter having a primary side in said first circuit and asecondary side in said second circuit, said fluid to be purified beinglocated in said first circuit and said second circuit comprising anadsorbent containing suspension of particles for binding said substancesto be eliminated, a first pump located in said first circuit forcirculation of the fluid to be purified, and a second pump located insaid second circuit for circulation of the adsorbent containingsuspension, wherein said second pump is drivable at a forwarding speedso that there is a passage of the substance containing fluid across saidat least one membrane filter between said first and second circuits,said pump in said second circuit being a means for achieving regionallyoccurring differentiable positive and negative transmembrane pressure onsaid membrane filter of 1-20 kPa wherein a fabric filter is providedafter the output of the primary side of the membrane filter.
 20. Anarrangement for the elimination of substances from a fluid to bepurified, comprisinga first and a second fluid circuit having at leastone membrane filter therebetween capable of allowing passagetherethrough of the substances to be eliminated, said membrane filterhaving a primary side in said first circuit and a secondary side in saidsecond circuit, said fluid to be purified being located in said firstcircuit and said second circuit comprising an adsorbent containingsuspension of particles for binding said substances to be eliminated, afirst pump located in said first circuit for circulation of the fluid tobe purified, and a second pump located in said second circuit forcirculation of the adsorbent containing suspension, wherein said secondpump is drivable at a forwarding speed so that there is a passage of thesubstance containing fluid across said at least one membrane filterbetween said first and second circuits, said pump in said second circuitbeing a means for achieving regionally occurring differentiable positiveand negative transmembrane pressure on said membrane filter, whereinthere is provided a detector located in said first circuit after theoutput of the primary side of the membrane filter, for noting defects insaid filter wherein, in the first circuit after the output of theprimary side of the membrane filter, there is provided a magnetic field,and a trap arrangement, and wherein particles of the adsorbentsuspension contain a magnetically active substance whereby, in theinstance of a defect in the membrane filter, particles, which intrudeinto the primary side, are captured by said trap arrangement.
 21. Thearrangement according to claim 20 wherein the second pump runs incountercurrent fashion relative to said first pump.
 22. The arrangementaccording to claim 20 wherein the second pump has a forwarding capacityof between 0.5 to 6 l/min.
 23. The arrangement according to claim 20wherein the second pump has a forwarding capacity of between 1-3 l/min.24. The arrangement according to claim 20 wherein said second pump is acentrifugal pump.
 25. The arrangement according to claim 20 whereinthere is provided a third pump means having two equivalent forwardingarrangements which introduce into said second circuit and take outtherefrom equal amounts of adsorbent suspension for the exchange of usedsuspension with fresh suspension.
 26. The arrangement according to claim25 wherein there is additionally provided a fourth pump for theacceleration of passage of fluid across the membrane and a locking valveto prevent the mixing of the used and the fresh adsorbent suspension.27. The arrangement according to claim 20 wherein there is provided avalve arrangement for maintaining constant, volume in said secondcircuit.
 28. The arrangement according to claim 27 wherein there isadditionally provided a locking valve to prevent the mixing of used andfresh adsorbent suspension.
 29. The arrangement according to claim 27wherein there is additionally provided a fourth pump for theacceleration of passage of fluid across the membrane.
 30. Thearrangement according to claim 20 wherein all of the parts coming incontact with the adsorbent suspension are provided to be single usecomponents.
 31. The arrangement according to claim 30 wherein the pumpscomprise a reusable drive and a single use pump head.
 32. Thearrangement in accordance with claim 20 wherein the regionally occurringdifferentiable positive and negative transmembrane pressure on saidmembrane filter of 1-20 kPa.
 33. The arrangement in accordance withclaim 20 wherein pressure sensors are provided at at least one of theinputs and outputs of the membrane.
 34. The arrangement in accordancewith claim 20 wherein the adsorbent suspension comprises activesubstances which are introducible into the second circuit by an exchangeprocess, in addition to the particles for binding the relevantpathophysiological substances.
 35. The arrangement according to claim 20wherein there is provided an inlet and outlet in said second circuit,the inlet being in fluid communication with means for introducing freshadsorbent suspension into said second fluid circuit and the outlet beingin fluid communication with means for taking out therefrom an equalamount of used suspension for the exchange of used suspension with freshsuspension.
 36. The arrangement according to claim 35 wherein the meansfor introducing fresh adsorbent suspension and taking out usedsuspension having pump means.
 37. The arrangement according to claim 35wherein the means for introducing fresh adsorbent suspension and takingout used suspension having valve means.
 38. The arrangement according toclaim 35 wherein there is provided a locking valve in said second fluidcircuit between the inlet and outlet of said second fluid circuit toprevent the mixing of the fresh and the used adsorbent suspension. 39.The arrangement according to claim 35 wherein there is provided a pumpmeans in said second fluid circuit between the inlet and outlet of saidsecond fluid circuit for the acceleration of passage of fluid across themembrane.
 40. An arrangement for the elimination of substances from afluid to be purified, comprisinga first and a second fluid circuithaving at least one membrane filter therebetween capable of allowingpassage therethrough of the substances to be eliminated, said membranefilter having a primary side in said first circuit and a secondary sidein said second circuit, said fluid to be purified being located in saidfirst circuit and said second circuit comprising an adsorbent containingsuspension of particles for binding said substances to be eliminated, afirst pump located in said first circuit for circulation of the fluid tobe purified, and a second pump located in said second circuit forcirculation of the adsorbent containing suspension, wherein said secondpump is drivable at a forwarding speed so that there is a passage of thesubstance containing fluid across said at least one membrane filterbetween said first and second circuits, said pump in said second circuitbeing a means for achieving regionally occurring differentiable positiveand negative transmembrane pressure on said membrane filter, whereinthere is provided a detector located in said first circuit after theoutput of the primary side of the membrane filter, for noting defects insaid filter wherein two membrane filters are provided, the membrane ofeach filter having a primary side and a secondary side, the primary sideof the first membrane filter and the primary side of the secondarymembrane filter are connected in series by as first connection conduitand the secondary side of the first membrane filter and the secondaryside of the second membrane filter are connected in series by a secondconnection conduit.
 41. The arrangement accordance to claim 40 whereinthere is provided a controllable clamp in said connection conduit ofsaid second circuit.
 42. An arrangement for the elimination ofsubstances from a fluid to be purified, comprisinga first and a secondfluid circuit having at least one membrane filter therebetween capableof allowing passage therethrough of the substances to be eliminated,said membrane filter having a primary side in said first circuit and asecondary side in said second circuit, said fluid to be purified beinglocated in said first circuit and said second circuit comprising anadsorbent containing suspension of particles for binding said substancesto be eliminated, a first pump located in said first circuit forcirculation of the fluid to be purified, and a second pump located insaid second circuit for circulation of the adsorbent containingsuspension, wherein said second pump is drivable at a forwarding speedso that there is a passage of the substance containing fluid across saidat least one membrane filter between said first and second circuits,said pump in said second circuit being a means for achieving regionallyoccurring differentiable positive and negative transmembrane pressure onsaid membrane filter, wherein there is provided a detector located insaid first circuit after the output of the primary side of the membranefilter, for noting defects in said filter wherein a fabric filter isprovided after the output of the primary side of the membrane filter.